Clinical Trials

Date: 2018-07-24

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 22nd International AIDS Conference (AIDS 2018)

Company: Merck&Co (USA - NJ)

Product: doravirine (MK-1439)

Action mechanism:

• non-nucleoside reverse transcriptase inhibitor. Doravirine is an investigational non-nucleoside reverse transcriptase inhibitor being evaluated for the treatment of HIV-1 infection. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and the ability to be dosed with or without food.

Disease: HIV-1 infection

Therapeutic area: Infectious diseases

Country: Australia, Austria, Canada, Chile, Denmark, France, Germany, Italy, Puerto Rico, Romania, Russian Federation, South Africa, Spain, UK, USA

Trial details:

• DRIVE-FORWARD is a multicenter, double-blind, randomized non-inferiority trial in which 766 treatment-naïve adults with HIV-1 infection received either 100 mg doravirine or 800 mg darunavir plus 100 mg ritonavir, both administered orally once-daily in combination with either FTC/TDF or ABC/3TC. The primary endpoint of the clinical trial was the proportion of participants with HIV-1 RNA copies of less than 50 copies/mL at Week 48. There were a number of secondary endpoints, including efficacy at Week 96, an evaluation of the effects of DOR and DRV+r on fasting serum lipids, change from baseline in CD4+ T-cell count, and evaluation of safety and tolerability. (NCT02275780)

Latest news:

• • On July 24, 2018, Merck&co announced Week 96 results from the Phase 3 DRIVE-FORWARD clinical trial evaluating the efficacy and safety of doravirine (DOR) in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history (treatment-naïve). At Week 96, 73.1 percent (277/379) of the group treated with once-daily DOR achieved viral suppression as measured by the proportion of patients who achieved HIV-1 RNA of less than 50 copies/mL, compared to 66.0 percent (248/376) of the group treated with once-daily ritonavir-boosted darunavir (DRV+r) (treatment difference: 7.1%, 95% confidence interval: 0.5, 13.7). These study results were presented  as a late-breaking abstract at the 22nd International AIDS Conference (AIDS 2018) taking place July 23-27, 2018, in Amsterdam.
• Data from DRIVE-FORWARD : In DRIVE-FORWARD, 766 participants (n=383 in each treatment group) with no antiretroviral treatment history were randomized and received either DOR (100 mg) once daily or DRV+r (800 mg and 100 mg, respectively) once daily, each in combination with FTC/TDF or ABC/3TC selected by the investigator. In this trial, after 96 weeks of treatment, the proportion of participants achieving HIV-1 RNA less than 50 copies/mL was 73.1 percent (277/379) in the DOR group and 66.0 percent (248/376) in the DRV+r group (treatment difference: 7.1%, 95% confidence interval: 0.5, 13.7). Results for participants with high baseline viral load (HIV-1 RNA greater than 100,000 copies/mL) were 65.4 percent (51/78) for DOR and 65.2 percent (43/66) for DRV+r (treatment difference: -1.1%, 95% confidence interval: -17.6, 15.3). In addition, the mean change from baseline in CD4+ T-cell count at 96 weeks was 224 cells/mm3 for DOR and 207 cells/mm3 for DRV+r (treatment difference: 17.4 cells/mm3, 95% confidence interval: -14.5, 49.3). In terms of resistance, two participants in the DOR treatment group (15 with successful genotype test) developed genotypic and phenotypic resistance to DOR through 96 weeks of treatment.
• The most common adverse events occurring in greater than or equal to 10 percent of participants in either treatment group through 96 weeks were diarrhea (DOR 17.0% [65/383], DRV+r 23.8% [91/383]), nausea (DOR 11.7% [45/383], DRV+r 13.6% [52/383]), headache (DOR 14.9% [57/383], DRV+r 12.0% [46/383]), upper respiratory tract infection (DOR 13.3% [51/383], DRV+r 7.8% [30/383]), and viral upper respiratory tract infection (DOR 11.5% [44/383] and DRV+r 13.1% [50/383]). The rate of discontinuation of therapy due to adverse events was 1.6 percent (6/383) in the DOR group and 3.4 percent (13/383) in the DRV+r group.
• At Week 96 mean changes from baseline in fasting serum blood lipids for the DOR and DRV+r treated groups in levels of low density lipoprotein cholesterol (LDL-C) were DOR -0.4 mg/dL and DRV+r 14.0 mg/dL (treatment difference: -14.6, 95% confidence interval: -18.2, -11.0); and in levels of non-high density lipoprotein cholesterol (non-HDL-C) were DOR -0.5 mg/dL and DRV+r 17.7 mg/dL (treatment difference: -18.4, 95% confidence interval: -22.5, -14.3). Mean changes from baseline in total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides for the DOR-treated group and the DRV+r treated group were 4.1 mg/dL and 21.9 mg/dL (treatment difference: -18.1, 95% confidence interval: -22.5, -13.7), 4.5 mg/dL and 4.2 mg/dL (treatment difference: 0.4, 95% confidence interval: -1.3, 2.1), and -1.1 mg/dL and 22.5 mg/dL (treatment difference: -25.7, 95% confidence interval: -36.6, -14.7), respectively.
• Previously, the findings at Week 48 demonstrated that once-daily DOR met its primary efficacy endpoint of non-inferiority compared to DRV+r, each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC). These data were presented at the Conference on Retroviruses and Opportunistic Infections in 2017.
• • On February 14, 2017, Merck&Co announced results of a pivotal Phase 3 clinical trial evaluating the safety and efficacy of doravirine (MK-1439). The study met its primary efficacy endpoint of the proportion of participants achieving levels of HIV-1RNA less than 50 copies/mL after 48 weeks of treatment, demonstrating the non-inferiority of once-daily doravirine (DOR) to once-daily ritonavir-boosted darunavir (DRV+r), each administered with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC), in previously untreated (treatment-naïve) adults with HIV-1 infection. In addition, a secondary endpoint showed that the DOR-treated group had statistically significant lower levels of fasting low density lipoprotein cholesterol (LDL-C), versus the DRV+r group. Findings from the ongoing “DRIVE-FORWARD” Phase 3 trial following 48 weeks of treatment were presented as a late-breaking abstract at the annual Conference on Retroviruses and Opportunistic Infections (CROI) being held in Seattle from Feb. 13-16, 2017.
• In the trial, after 48 weeks of treatment, the proportion of participants achieving levels of HIV-1 RNA less than 50 copies/mL following once-daily DOR (100 mg) or once-daily DRV+r (800 mg and 100 mg respectively), each in combination with either TDF/FTC or ABC/3TC, was 83.8 percent (321/383) and 79.9 percent (306/383), respectively; with a treatment difference (95 % confidence interval) of 3.9 [-1.6, 9.4]. Increases in mean CD4+ T-cell counts from baseline were similar for the DOR and DRV+r treatment groups: 193 and 186 cells/mm3, respectively.
• In addition, comparable efficacy was observed for participants with baseline levels of HIV-1 RNA greater than 100,000 copies/mL: 81.0 percent (64/79) for DOR and 76.4 percent (55/72) for DRV+r; with a treatment difference (95% confidence interval) of 3.0 [-11.2, 17.1]. One out of 383 participants developed phenotypic and genotypic resistance in the DOR arm (the patient came off study at Week 24 because of non-adherence). None of the 383 participants receiving DRV+r developed phenotypic and genotypic resistance.
• The rates of reported adverse drug reactions were 31 percent (117/383) for DOR and 32 percent (123/383) for DRV+r. Discontinuations due to adverse events for the DOR and DRV+r treatment groups were 2 percent (6/383) and 3 percent (12/383), respectively. The most common adverse events for DOR and DRV+r (occurring in greater than or equal to 10 percent of participants) were: diarrhea (14% vs. 22%); headache (14% vs. 11%); nausea (11% vs. 12%) and nasopharyngitis (8% vs. 10 %), respectively.
• Analysis of fasting serum blood lipids for the DOR and DRV+r treated groups showed a statistically significant difference (p<0.0001) in mean changes from baseline in the levels of LDL-C (-4.5 mg/dL vs. +9.9 mg/dL) and non-high density lipoprotein cholesterol (non-HDL-C) (-5.3 mg/dL vs. +13.8 mg/dL), respectively. Mean changes from baseline in total cholesterol, high density lipoprotein cholesterol (HDL-C) and triglycerides for the DOR- treated group and the DRV+r- treated group were -1.4 mg/dL, +3.9 mg/dL, and -3.1 mg/dL vs. +17.9 mg/dL, +4.2 mg/dL, and +22 mg/dL, respectively.

     

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